Alpha-glucosidase inhibitors

ABSTRACT

Novel α-Glucosidase inhibitors include propanone substituted indole ring-containing heterocyclic compounds, which are represented by Formula I: 
     
       
         
         
             
             
         
       
     
     Wherein
         R 1  is thiophene, 2,4-di chloro phenyl, 2,6-di chloro phenyl, bromo phenyl, benzyl or nitrophenyl; and R 2  is an aryl group, or stereoisomers or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to indole ring-containing heterocycliccompounds, and particularly to propanone-substituted indolering-containing heterocyclic compounds, as novel α-glucosidaseinhibitors.

2. Description of the Related Art

Indoles form a large class of heterocyclic compounds, found in manynatural products, such as alkaloids, fungal metabolites and marinenatural products. Indole myriad derivatives have therefore captured theattention of organic synthetic chemists. Indole and its analogs areknown to possess a wide spectrum of biological activities. Severalindole derivatives were reported as anticancer, antibacterial,anti-ulcerative, anti-platelet, anti-malarial, anti-leishmanial,antiviral, antioxidant, anti-rheumatoidal, anti-HIV, immunomodulator,anti-tubercular, inhibitors of chemical mediator's release andleukotriene B₄ tyrosinase and aldose (reductase activity).

Some of these compounds also possess anti-inflammatory and analgesicproperties. They play a vital role in the immune system. Many indolederivatives are potent scavengers of free radicals. The immensebiological activities of indole derivatives led to vigorous research todevelop and optimize highly efficient arid economical synthetic routstowards novel biologically active indole substances. In this regard,asymmetric synthesis is one of the most promising approaches foraccessing enantio-pure compounds, including diverse indole derivatives.

Glucosidases are also involved in several important biologicalprocesses, such as the synthesis of glycoproteins and the lysosomalcatabolism of glycol conjugates. In addition, α-glucosidase inhibitorshave been also used as inhibitors of tumor metastasis, and asanti-obesity drugs, fungi static compounds, insect's anti-feedants,anti-viral and immune modulators. The inhibition of α-glucosidase isreported mainly to overcome the risk of postprandial hyperglycemia indiabetic patients, which in turn is associated with cardiovascular andother health disorders. 1-Deoxynojirimycin, acarbose, miglitol, etc.have been developed as α-glucosidase inhibitors. However, many of themhave adverse effects and low patient tolerability. Therefore, there isan urgent need for safe and effective α-glucosidase inhibitors tocontrol diabetic and cardiovascular complications due to hyperglycemia.

Thus, novel α-glucosidase inhibitors incorporating an indole moietysolving the aforementioned problems is desired.

SUMMARY OF THE INVENTION

According to one aspect, there is provided novel α-glucosidaseinhibitors incorporating an indole moiety, represented by Formula 1

Formula 1

Wherein:

R₁ is thiophene, 2,4-di chloro phenyl, 2,6-di chloro phenyl, bromophenyl, benzyl or nitrophenyl and R₂ is an aryl group or stereoisomersor pharmaceutically acceptable salts thereof.

Additionally, a method for preparing the α-glucosidase inhibitors ofFormula 1 includes:

(a) Mixing a solution of Cu(OTf)₂ and a ligand in dry acetonitrile underan inert atmosphere to form a first mixture;(b) Adding to the first mixture a solution of indole and a conjugatedketone in dry acetonitrile to form a reaction mixture;(c) Stirring the reaction mixture at ambient temperature for about 24hours to about 48 hours.(d) Removing a solvent from the reaction mixture in vacuo.(e) Extracting the mixture using an organic solvent, washing with brineand drying over MgSO₄.

The compounds represented by Formula I are useful in treating orpreventing disorders related to postprandial hyperglycemia in diabeticpatients and associated complications of diabetes such as microvascularcomplications (e.g., retinopathy, neuropathy, nephropathy and delayedwound healing).

These and other features of the present invention will become readilyapparent upon further review of the following specification anddrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The sole drawing FIGURE shows a schematic representation of thesynthesis of indole derivatives (Compounds 3a-r), according to thepresent invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Novel α-glucosidase inhibitors include propanone-substituted indole ringcontaining compounds of Formula I shown below.

Where in

R₁ is thiophene, 2,4-di chloro phenyl, 2,6-di chloro phenyl, bromophenyl, methyl benzene or nitrophenyl and R₂ is an aryl groups orstereoisomers or pharmaceutically acceptable salts thereof.

The present inventors have evaluated the in vitro α-glucosidaseinhibitory activity of the propanone-substituted indole ring containingcompounds of Formula I as well as other propanone-substituted indolering containing compounds. The present inventors have found thatpropanone-substituted indole ring containing compounds representedgenerally by Formula II (shown below) exhibit in vitro α-glucosidaseinhibitory activity. The compounds represented by Formula II includecompounds having the following chemical formula:

Where in

R₁ and R₂ are independently selected from the group consisting of aphenyl group, a benzyl group, a thiophene group, and a naphthyl group,and are unsubstituted or substituted with one or more substituentsselected from a halogen, straight or branched chain alkyl group having 1to 3 carbon atoms, alkoxy, nitro, or hydroxyl group or stereoisomers orpharmaceutically acceptable salts thereof.

It should be noted that Formula I compounds fall within the definitionof Formula II compounds. The particular compounds of Formula I and/orFormula II synthesized and evaluated for in vitro α-glucosidaseinhibitory activity are listed in Table 1 below.

TABLE 1 Compounds 3a-r Compound R₁ R₂ 3a

3b

3c

3d

3e

3f

3g

3h

3i

3j

3k

3l

3m

3n

3o

3p

3q

3r

The α-glucosidase inhibitors listed in Table 1 (Compounds 3a-3r) wereprepared in moderate to good chemical yields with excellentenantioselectivity (up to 99.9%). These compounds 3a-r were identifiedas potent α-glucosidase enzyme inhibitors. All of these compounds werefound to be several folds more active than the standard drug acarbose inin vitro biochemical assay.

β-Glucuronidase is a lysosomal enzyme that cleaves β-glucuronic acidlinkages from the non-reducing termini of glycosaminoglycans, such aschondroitin sulfate, heparin sulfate, and hyaluronic acid. α-Glucosidaseis a small intestinal membrane bound enzyme that catalyzes thehydrolysis of disaccharides to absorbable monosaccharide, i.e., glucose,and thus suppress the postprandial hyperglycemia. Inhibition ofα-glucosidase can effectively overcome the risk of postprandialhyperglycemia, an independent risk factor of cardiovascular diseases.

All of the synthesized compounds 3a-r were evaluated for their in vitroα-glucosidase enzyme inhibition activity. The series compounds 3a-rexhibited a potent α-glucosidase inhibition with IC₅₀ values 43.3±0.92,17.6±0.98, 25.2±1.96, 24.0±4.0, 27.1±0.69, 15.2±0.58, 43.9±0.51,37.9±0.86, 15.1±0.4, 18.1±1.90, 21.8±0.25, 15.6±0.17, 4.3±0.13,26.3±0.48, 11.8±0.06, 34.6±1.55, 24.9±1.61, and 33.2±0.75 μM,respectively. All tested compounds were found to be several fold moreactive than the standard drug, acarbose (IC₅₀=840±1.73 μM). Compound 3ghaving 3-naphthyl-1-phenylpropan-1-one moiety attached to indole ring,was found to be the least active in the series with IC₅₀ value 43.9±0.51μM. However the activity increased when the phenyl ring of1,3-diphenylpropan-1-one moiety was substituted with chloro atoms, asobserved in compounds 3m (IC₅₀=4.3±0.13 μM) and 3l (IC₅₀=15.6±0.17 μM).

The substitution of the same phenyl ring with electron donating methoxysubstituent also contributed in increasing the activity of compound 3e(IC₅₀=27.1±0.69 μM). Compounds 3b and 3f were found to be the mostpotent α-glucosidase inhibitors of the series with the IC₅₀ values17.6±0.98 and 15.2±0.58 μM, respectively. The activity seems to be dueto the presence of a naphthalene ring attached to the propan-1-onemoiety, in place of phenyl. The comparison of activities of compounds 3e(IC₅₀=27.1±0.69 μM) and 3f (IC₅₀=15.2±0.78 μM) further support theinitial inference that naphthalene moiety contributes more in theactivity. The results are summarized in Table-2.

TABLE 2 Results of α-glucosidase inhibition assay on compounds 3a-rCompounds α-Glucosidase Inhibition (IC₅₀ in μM) 3a 43.3 ± 0.92 3b 17.6 ±0.98 3c 25.2 ± 1.96 3d 24.0 ± 4.0  3e 27.1 ± 0.69 3f 15.2 ± 0.58 3g 43.9± 0.51 3h 37.9 ± 0.86 3i 15.1 ± 0.4  3j 18.1 ± 1.90 3k 21.8 ± 0.25 3l15.6 ± 0.17 3m  4.3 ± 0.13 3n 26.3 ± 0.48 3o 11.8 ± 0.06 3p 34.6 ± 1.553q 24.9 ± 1.61 3r 33.2 ± 0.75 Std. Acarbose  840 ± 1.73

The present compounds can be incorporated into pharmaceuticalcompositions suitable for administration, together with apharmaceutically acceptable carrier or excipient. Such compositionstypically comprise a therapeutically effective amount of any of thecompounds above, and a pharmaceutically acceptable carrier. Preferably,the effective amount when treating postprandial hyperglycemia indiabetic patients is an amount effective to inhibit α-glucosidaseactivity and less than an amount which causes toxicity in a patient.

A typical synthetic strategy was employed to obtain the title compounds3a-r in moderate to good yields (22-89%) with excellentenantioselectivities up to 99.9% ee, as presented in FIG. 1. In thepresent investigation, the chiral Lewis acid catalysts, prepared fromoxazoline-imidazoline-type ligands (L) and Cu(OTf)₂ as metal salt, wasused. This modified ligand catalyst was employed in the asymmetriccatalytic Friedel-Crafts alkylation of indole1 with enones (Z)-(2a-r) toafford the product (S)-3-(1H-indol-3-yl)propan-1-ones (3a-r). Eighteenderivatives were prepared using the optimized conditions which describedin our earlier publications. The absolute configuration of the products3a-r were assigned as (S) by optical correlation with those reported inthe literature.

Referring to the sole drawing FIGURE, the synthetic strategy is asfollows. A solution of Cu(OTf)₂ (15 mg, 0.042 mmol, 20 mol %) and chiralligand L (17 mg, 0.042 mmol, 10 mol %) in dry CH₃CN (2 mL) is stirredfor 1 hour at room temperature under argon atmosphere. To the resultingblue-green solution, a solution of indole (1) (50 mg, 0.425 mmol) andconjugated ketones (Compounds 2a-r) (0.425 mmol) in dry CH₃CN (1 mL) isadded via syringe. The reaction mixture is then stirred at ambienttemperature for 24-48 hours. The reaction is monitored by TLC until thestarting material is completely consumed, then the solvent is removedunder vacuum. Water (10 mL) is added and the mixture is extracted withEtOAc (2×25 mL), washed with brine (10 mL), and dried over MgSO₄. Theproduct can be purified by column chromatography.

The Lewis acid-catalyzed enantioselective Friedel-Crafts alkylation ofprochiral α,β-unsaturated enones are the key precursors towards thesynthesis of various classes of compounds, including indole containingenone moieties. Their building blocks provide important andstraightforward strategies to access structurally elaborated andoptically pure molecules. It is envisaged that the novel pharmacophoreas represented by the reaction in FIG. 1 would generate novel molecularentities, which are likely to exhibit interesting biological propertiesin animal models.

The newly synthesized α-glucosidase inhibitors may be utilized bymedicinal chemists as structural templates to further improve biologicalactivities. The potent α-glucosidase inhibiting activities of thesecompounds indicate their potential as possible drug candidates for thetreatment of hyperglycemia and associated diabetic and cardiovascularcomplications and related health disorders. Thus, the discovery of newindole derivatives as α-glucosidase inhibitors can open up new vistasfor further research in this important field as this enzyme is activelyinvolved in the on-set of diabetic, and cardiovascular complications.

The following examples will further illustrate the synthetic processesof making the enantiomerically pure indole derivatives 3a-r viaFriedel-Crafts alkylation of indole 1 with enones 2a-r.

Example 1 Assay Protocol for α-Glucosidase Inhibition (In Vitroα-Glucosidase Inhibition Assay)

α-Glucosidase inhibition assay was performed spectrophotometrically.α-Glucosidase from Saccharomyces cervisiae was dissolved in phosphatebuffer (pH 6.8, 50 mM). Test compounds were dissolved in 70% DMSO. In96-well plates, 20 μL of test sample, 20 μL of enzyme and 135 μL ofbuffer were added and incubated for 15 minutes at 37° C. Afterincubation, 25 μL, of p-nitrophenyl-α-D-glucopyranoside (0.7 mM, SigmaAldrich) was added and the change in absorbance was monitored for 30minutes at 400 nm. Test compound was replaced by DMSO (7.5% final) ascontrol. Acarbose (Acarbose, Sigma Aldrich) was used as a standardinhibitor.

The products were isolated in a moderate to excellent yields (up to 89%)with excellent enantioselectivities (up to 99.9%). These compounds 3a-rwere evaluated for their in vitro α-glucosidase inhibitory activity andfound to be potent inhibitors as discussed infra.

Example 2 Synthesis of(S)-4-Isopropyl-2-(3-((S)-4-isopropyl-1-(4-methoxyphenyl)-4,5-dihydro-1H-imidazol-2-yl)pentan-3-yl)-4,5-dihydrooxazole(L)

The ligand L was prepared by following the procedure described byBarakat et al. “Highly Enantioselective Friedel-Crafts alkylations ofIndoles with α,β-unsaturated Ketones under Cu(II)-simpleOxazoline-Imidazoline Catalysts,” Tetrahedron, 69: 5185-5192, 2013. Theproduct L was obtained as slightly yellowish colored oily product (470mg, 58.9%). ¹H-NMR (CDCl₃, 400 MHz) δ 0.71-0.99 (m, 18H, 2CH ₃CH₂ &2(CH₃)₂CH), 1.59-1.72 (m, 1H, (CH₃)₂CH, imidazole), 1.73-1.85 (m, 1H,(CH₃)₂CH, oxazole), 1.85-2.10 (m, 4H, CH₃CH ₂), 3.38-3.50 (m, 2H, NCH₂CH, imidazole), 3.58-3.72 (m, 1H, OCH_(2(a))CH, oxazole), 3.72-3.77 (m,1H, OCH_(2(b))CH, oxazole), 3.79 (s, 3H, ArOCH₃), 3.87-3.96 (m, 1H,NCH₂CH(CH₃)₂, imidazole), 4.06-4.19 (m, 1H, OCH₂CH(CH₃)₂, oxazole), 6.80(d, 2H, J=8.8 Hz, ArH) and 7.06 (d, 2H, J=8.8 Hz, ArH). The otheranalytical data are in accordance with the literature.

Example 3 Preparation of (S)-3 (1H-Indol-3-yl)-1,3-diphenylpropan-1-one(3a)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and chalcone2a (89 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica gel column (EtOAc/hexanes 1:9)yielded compound 3a as a white solid (119 mg, 86%). This was identifiedas a known compound on the basis of spectral comparison. Enantiomericexcess was determined by chiral HPLC (Chiracel OD-H column),hexanes:i-PrOH 80:20, 0.4 mL/min, λ=220 nm, t_(r)(minor)=8.73 min,t_(r)(major)=9.68 min, to be 99.92%; m.p. 147-149° C., [α]²⁵ _(D)=+29.6(c, 0.45, CHCl₃) [lit. [23a] m.p. 148-152° C., [α]²⁵ _(D)+25.3 (c, 0.3,CHCl₃)]; [Anal. calcd. for C₂₃H₁₉NO: C, 84.89; H, 5.89; N, 4.30. FoundC, 85.17; H, 5.63; N, 4.42]. IR (cm⁻¹): 3413, 1679, 1597, 1451, 745,698; ¹H-NMR (CDCl₃, 400 MHz) δ 3.73-3.80 (m, 2H, COCH ₂), 5.07 (t, 1H,J=6.6 Hz, ArCHCH₂), 6.99 (s, 1H, CHNH), 7.25-7.44 (m, 11H, ArH), 7.92(d, J=7.3 Hz, 1H of 4H-indole & 2H of COPhH _(ortho)), 7.96 (s, 1H, NHof Indole); ¹³C-NMR (CDCl₃, 100 MHz): δ 38.29, 45.28, 111.18, 119.4,119.5, 119.6, 121.5, 122.2, 126.4, 126.5, 127.9, 128.2, 128.5, 128.7,133.1, 136.6, 137.1, 144.3, 198.62; LC/MS (ESI): M⁺, found m/z 325.15,C₂₃H₁₉NO requires 325.15.

Example 4 Preparation of(S)-3-(4-Chlorophenyl)-3-(1H-indol-3-yl)-1-(naphthalen-2-yl)propan-1-one(3b)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2b(124 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP2.Purification by chromatography on silica (EtOAc/hexane 1:9) yieldedcompound 3b as a light yellow solid (141 mg, 81%). Enantiomeric excesswas determined by chiral HPLC (Chiracel OD-H column), hexane:i-PrOH80:20, 0.4 mL/min, λ=220 nm, t_(r)(minor)=8.80 min, t_(r)(major)=9.73min, to be 95.6%; m.p. 237-241° C., [α]_(D) ²⁵=+19.1 (c, 0.45, CHCl₃);[Anal. calcd. for C₂₇H₂₀ClNO: C, 79.11; H, 4.92; N, 3.42. Found C,79.35; H, 5.02; N, 3.59]. IR (KBr): 3409, 2923, 1677, 815, 744, 476cm⁻¹; ¹H-NMR (CDCl₃, 400 MHz) δ 3.75-3.86 (m, 1H, COCH _(2(a))),3.86-3.98 (m, 1H, COCH _(2(b))), 5.09 (t, 1H, J=7.3 Hz, ArCHCH₂),7.01-7.07 (m, 2H, ArH), 7.14-7.38 (m, 7H, ArH), 7.38-7.46 (m, 1H, ArH),7.48-7.66 (m, 2H, ArH), 7.83-7.91 (m, 2H, ArH), 7.91-7.99 (m, 2H, ArH),8.42 (s, 1H, NH of Indole); ¹³C-NMR (CDCl₃, 100 MHz): δ 28.5, 45.0,111.1, 119.0, 119.5, 121.1, 122.0, 123.9, 124.6, 126.5, 128.1, 128.2,128.6, 128.7, 129.3, 132.0, 133.8, 134.1, 135.2, 136.7, 137.0, 139.8,142.7, 199.9; LC/MS (ESI): M⁺, found m/z 409.09, C₂₇H₂₀ClNO requires409.12.

Example 5 Preparation of(S)-3-(1H-Indol-3-yl)-3-mesityl-1-phenylpropan-1-one (3c)

Oxazoline-imidazoline ligand L (25 mg, 15 mol %), Cu(OTf)₂ (22 mg, 30mol %), indole (50 mg, 0.425 mmol) and enone 2c (107 mg, 0.425 mmol) inCH₃CN (3 mL) were reacted according to GP2. Purification bychromatography on silica gel column (EtOAc/hexanes 1:9) yielded compound3c as a light yellow solid (63 mg, 40%). Enantiomeric excess wasdetermined by chiral HPLC (Chiracel OD-H), hexane:i-PrOH 80:20, 0.4mL/min, λ=220 nm, t_(r)(minor)=18.9 min, t_(r)(major)=23.0 min, to be96%; m.p. 169-171° C., [α]_(D) ²⁵=+11.5 (c, 0.45, CHCl₃); [Anal. calcd.for C₂₆H₂₅NO: C, 84.98; H, 6.86; N, 3.81. found C, 85.11; H, 6.73; N,3.75]. IR (KBr): 3409, 2921, 1677, 1451, 744, 690 cm⁻¹; ¹H-NMR (CDCl₃,400 MHz) δ 2.27 (s, 9H, ArCH ₃), 3.57-3.63 (m, 1H, COCH _(2(a))),4.05-4.12 (m, 1H, COCH _(2(a))), 5.49 (t, 1H, J=6.6 Hz, ArCHCH₂), 6.81(s, 2H, Me₃PhH), 6.85-6.94 (m, 1H, ArH), 6.94-7.02 (m, 1H, ArH),7.02-7.15 (m, 1H, ArH), 7.20-7.36 (m, 2H, ArH), 7.41-7.50 (m, 2H, ArH),7.50-7.59 (m, 1H, ArH), 7.90 (s, 1H, NH of Indole), 7.98 (d, J=7.3 Hz,2H, ArH _(ortho)); ¹³C-NMR (CDCl₃, 100 MHz): δ 20.9, 21.4, 29.8, 33.2,43.0, 111.09, 117.8, 118.7, 119.1, 119.9, 121.7, 122.1, 127.0, 128.2,128.3, 128.8, 130.0, 138.8, 136.8, 137.2, 137.3, 199.24; LC/MS (ESI):M⁺, found m/z 367.17, C₂₆H₂₅NO requires 367.19.

Example 6 Preparation of(S)-3-(1H-Indol-3-yl)-1-phenyl-3-(p-tolyl)propan-1-one (3d)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2d(95 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica gel column (EtOAc/hexanes 1:9)yielded compound 3d as yellow solid (105 mg, 73%). Enantiomeric excesswas determined by chiral HPLC (Chiracel OD-H), hexanes:i-PrOH 80:20, 0.4mL/min, λ=220 nm, tr(minor)=27.3 min, tr(major)=31.2 min, to be 95.8%;m.p. 153-155° C., [α]^(D) ₂₅=+14.6 (c, 0.45, CHCl₃[Anal. calcd. forC₂₄H₂₁NO: C, 84.92; H, 6.24; N, 4.13. Found C, 84.66; H, 6.15; N, 3.97].IR (KBr): 3413, 1680, 1452, 743, 689 cm⁻¹; ¹H-NMR (CDCl₃, 400 MHz) δ2.26 (s, 3H, ArCH ₃), 3.65-3.78 (m, 1H, COCH _(2(a))), 3.78-3.89 (m, 1H,COCH _(2(b))), 5.02 (t, 1H, J=7.4 Hz, ArCHCH₂), 6.98-7.61 (m, 12H, ArH),7.89 (s, 1H, NH of Indole), 7.93 (d, J=7.3 Hz, 2H of COPhH _(ortho) );¹³C-NMR (CDCl₃, 100 MHz): δ 21.1 (ArCH₃), 37.9 (ArCHCH₂), 45.4(ArCHCH₂), 111.2, 119.4, 119.5, 119.6, 121.6, 122.2, 126.9, 127.8,128.2, 128.7, 129.4, 133.3, 135.8, 136.7, 137.1, 141.3, 198.71; LC/MS(ESI): M⁺, found m/z 339.19, C₂₄H₂₁NO requires 339.16.

Example 7 Preparation of(S)-3-(1H-Indol-3-yl)-3-(4-methoxyphenyl)-1-phenylpropan-1-one (3e)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2e(101 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica gel column (EtOAc/hexane 1:9)yielded compound 3e as a yellow solid (134 mg, 89%). Enantiomeric excesswas determined by HPLC (Chiracel OD-H), hexanes:i-PrOH 80:20, 0.4mL/min, λ=220 nm, tr(minor)=20.1 min, tr(major)=24.0 min, to be 96.4%;m.p. 134-136° C., [α]_(D) ²⁵=+21.4 (c, 0.45, CHCl₃); [Anal, calcd. forC₂₄H₂₁NO₂: C, 81.10; H, 5.96; N, 3.94. Found C, 80.79; H, 5.86; N,4.07]. IR (KBr): 3412, 2923, 1674, 1509, 1245, 1177, 746, 476 cm⁻¹;¹H-NMR (CDCl₃, 400 MHz) δ 3.73 (s, 3H, ArOCH ₃), 3.77-3.85 (m, 1H, COCH_(2(a))), 3.85-3.98 (m, 1H, COCH _((b))), 5.06 (t, 1H, J=7.4 Hz,ArCHCH₂), 6.78-7.83 (m, 2H, ArH), 6.97-7.05 (m, 2H, ArH), 7.11-7.19 (m,1H, ArH), 7.22-7.62 (m, 6H, ArH), 7.84-8.01 (m, 3H, ArH), 8.42 (s, 1H,NH of Indole); ¹³C-NMR (CDCl₃, 100 MHz): δ 37.8, 45.5, 55.3, 111.3,113.9, 119.7, 121.5, 122.0, 124.0, 126.8, 127.8, 128.5, 128.8, 129.6,132.4, 134.9, 135.8, 136.7, 158.1, 198.8; LC/MS (ESI): M⁺, found m/z355.19, C₂₄H₂₁NO₂ requires 355.16.

Example 8 Preparation of(S)-3-(1H-Indol-3-yl)-3-(4-methoxyphenyl)-1-(naphthalen-2-yl)propan-1-one(3f)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2f(123 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica gel column (EtOAc/hexanes 1:9)yielded compound 3f as an off white solid (112 mg, 66%). Enantiomericexcess was determined by chiral HPLC (Chiracel OD-H), hexane:i-PrOH80:20, 0.4 mL/min, λ=220 nm, tr(major)=39.4 min, tr(minor)=49.1 min, tobe 90.8%; m.p. 159-162° C., [α]²⁵ _(D)=+17.5 (c, 0.45, CHCl₃); [Anal.calcd. for C₂₈H₂₃NO₂: C, 82.94; H, 5.72; N, 3.45. Found C, 83.22; H,5.61; N, 3.73]. IR (KBr): 3413, 3007, 2930, 1679, 1610, 1509, 1246,1177, 1032, 745, 544 cm⁻¹; ¹H-NMR (CDCl₃, 400 MHz) δ 3.65-3.82 (m,2H+3H, COCH ₂& ArOCH ₃), 5.01 (t, 1H, J=7.3 Hz, ArCHCH₂), 6.75-6.83 (m,2H, ArH), 6.97-7.07 (m, 2H, ArH), 7.11-7.20 (m, 1H, ArH), 7.21-7.48 (m,8H, ArH), 7.49-7.56 (m, 1H, ArH), 7.91 (s, 1H, NH of Indole), 7.93 (s,2H. ArH); ¹³C-NMR (CDCl₃, 100 MHz): δ 37.5, 45.5, 55.3, 111.4, 113.8,116.2, 118.1, 119.7, 119.9, 121.6, 122.1, 123.4, 126.7, 127.0, 128.3,128.9, 130.1, 130.4, 131.9, 133.3, 135.2, 136.4, 136.7, 137.2, 158.0,198.8; LC/MS (ESI): M⁺, found m/z 405.18, C₂₈H₂₃NO₂ requires 405.17.

Example 9 Preparation of(S)-3-(1H-Indol-3-yl)-1-(naphthalen-2-yl)-3-phenylpropan-1-one (3g)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2g(110 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica (EtOAc/hexane 1:9) yieldedcompound 3g as a white solid (75 mg, 47%). Enantiomeric excess wasdetermined by chiral HPLC (Chiracel OD-H), hexane:i-PrOH 80:20, 0.4mL/min, λ=220 nm, t_(r)(minor)=12.0 min, t_(r)(major)=14.9 min, to be95.5%; m.p. 166-169° C., [α]_(D) ²⁵+24.2 (c, 0.45, CHCl₃); [Anal. calcd.for C₂₇H₂₁NO: C, 86.37; H, 5.64; N, 3.73. Found C, 85.98; H, 5.87; N,3.93]. IR (KBr): 3415, 1677, 1597, 1456, 746, 476 cm⁻¹; ¹H-NMR (CDCl₃,400 MHz) δ 3.83-3.91 (m, 1H, COCH _(2(a))), 3.91-3.95 (m, 1H, COCH_(2(b))), 5.13 (t, 1H, J=7.3 Hz, ArCHCH₂), 7.00-7.11 (m, 3H, ArH),7.11-7.23 (m, 2H, ArH), 7.23-7.50 (m, 6H, ArH), 7.50-7.63 (m, 2H, ArH),7.95-8.19 (m, 4H, ArH), 8.43 (s, 1H, NH of Indole); ¹³C-NMR (CDCl₃, 100MHz): δ 38.3, 45.3, 111.2, 116.0, 119.4, 119.5, 119.6, 121.5, 122.2,123.3, 125.1, 126.4, 126.6, 127.9, 128.2, 128.5, 128.7, 129.4, 131.0,133.0, 136.5, 137.1, 141.1, 144.3, 198.6; LC/MS (ESI): M⁺, found 375.15,C₂₇H₂₁NO requires 375.16.

Example 10 Preparation of(S)-3-(4-Chlorophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (3h)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2h(103 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica (EtOAc/hexane 1:9, R_(f)=0.75)yielded compound 3h as a light yellow solid (128.5 mg, 84%).Enantiomeric excess was determined by chiral HPLC (Chiracel OD-Hcolumn), hexane:i-PrOH 80:20, 0.4 mL/min, λ=220 nm, t_(r)(minor), =8.84min, t_(r)(major)=9.74 min, to be 93.85%; m.p. 189-192° C., [α]²⁵_(D)=+23.7 (c, 0.45, CHCl₃); [Anal. calcd. for C₂₃H₁₈ClNO: C, 76.77; H,5.04; N, 3.89. Found C, 76.92; H, 5.12; N, 3.71]. IR (cm⁻¹): 3369, 1677,745, 582, 502; ¹H-NMR (CDCl₃, 400 MHz) δ 3.64-3.38 (m, 2H, COCH ₂), 5.04(t, 1H, J=7.3 Hz, ArCHCH₂), 6.93-7.11 (m, 2H, ArH & 1H of NCH ofindole), 7.12-7.63 (m, 8H, ArH), 7.92 (d, J=7.3 Hz, 1H of 4H-indole & 2Hof COPhH _(ortho)), 7.99 (s, NH of Indole); ¹³C-NMR (CDCl₃, 100 MHz): δ29.8, 45.0, 113.3, 119.0, 119.9, 121.2, 123.3, 126.5, 128.1, 128.2,128.6, 128.7, 132.0, 133.8, 136.7, 137.0, 140.0, 142.8, 198.3; LC/MS(ESI): M⁺, found 359.10, C₂₃H₁₈ClNO requires 359.11.

Example 11 Preparation of(S)-3-(1H-Indol-3-yl)-3-mesityl-1-(naphthalen-2-yl)propan-1-one (3i)

Oxazoline-imidazoline ligand L (34 mg, 20 mol %), Cu(OTf)₂ (22 mg, 30mol %), indole (50 mg, 0.425 mmol) and enone 2i (129 mg, 0.425 mmol) inCH₃CN (3 mL) were reacted according to GP2. Purification bychromatography on silica (EtOAc/hexane 1:9) yielded compound 3i as ayellow solid (39 mg, 22%). Enantiomeric excess was determined by chiralHPLC (Chiracel OD-H), hexane:i-PrOH 80:20, 0.4 mL/min, λ=220 nm,t_(r)(minor)=18.8 min, t_(r)(major)=22.9 min, to be 97.8%; m.p. 227-229°C., [α]_(D) ²⁵=+17.3 (c, 0.45, CHCl₃); [Anal. calcd. for C₃₀H₂₇NO: C,86.30; H, 6.52; N, 3.35. Found C, 86.19; H, 6.61; N, 3.49]. IR (KBr):3410, 3319, 2652, 1653, 1619, 1590, 1457, 744 cm⁻¹; ¹H-NMR (CDCl₃, 400MHz) δ 2.27 (s, 9H, ArCH ₃), 3.68-3.78 (m, 1H, COCH _(2(a))), 4.17-4.23(m, 1H, COCH _(2(b))), 5.54 (t, 1H, J=6.6 Hz, ArCHCH₂), 6.79-6.92 (m,3H, ArH), 7.92-7.20 (m, 2H, ArH), 7.20-7.38 (m, 3H, ArH), 7.50-7.68 (m,2H, ArH), 7.84-7.98 (m, 3H, ArH), 8.05-8.08 (m, 1H, ArH), 8.47 (s, 1H,NH of Indole); ¹³C-NMR (CDCl₃, 100 MHz): δ 21.4, 21.5, 29.8, 33.4, 43.0,111.0, 115.8, 116.2, 117.6, 119.1, 119.3, 120.0, 121.5, 122.0, 123.2,124.1, 125.5, 127.1, 128.0, 128.5, 129.6, 131.0, 132.8, 134.6, 135.9,137.0, 137.3, 199.1; LC/MS (ESI): M⁺, found 417.22, C₃₀H₂₇NO requires417.21.

Example 12 Preparation of(S)-3-(1H-Indol-3-yl)-1-(naphthalen-2-yl)-3-(p-tolyl)propan-1-one (3j)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2j(116 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica (EtOAc/hexane 1:9) yieldedcompound 3j as a yellowish solid (45 mg, 27%). Enantiomeric excess wasdetermined by chiral HPLC (Chiracel OD-H), hexane:i-PrOH 80:20, 0.4mL/min, λ=220 nm, t_(r)(minor)=7.6 min, t_(r)(major)=9.7 min, to be93.4%; m.p. 174-177° C., [α]_(D) ²⁵=+9.1 (c, 0.45, CHCl₃); [Anal. calcd.for C₂₈H₂₃NO: C, 86.34; H, 5.95; N, 3.60. Found C, 86.24; H, 6.09; N,3.37]. IR (KBr): 3413, 2923, 2854, 1676, 1625, 1461, 816, 748, 476 cm⁻¹;¹H-NMR (CDCl₃, 400 MHz) δ 2.27 (s, 3H, ArCH ₃), 3.76-3.88 (m, 1H, COCH_(2(a))), 3.89-3.98 (m, 1H, COCH _(2(b))), 5.08 (t, 1H, J=7.3 Hz,ArCHCH₂), 6.87-7.45 (m, 7H, ArH), 7.55-7.71 (m, 3H, ArH), 7.83-8.02 (m,6H, ArH), 8.42 (s, 1H, NH of Indole); ¹³C-NMR (CDCl₃, 100 MHz): δ 21.1,38.1, 45.4, 111.2, 116.1, 118.0, 119.5, 122.2, 123.8, 124.2, 125.8,126.7, 127.8, 128.4, 129.2, 129.8, 132.2, 134.1, 135.9, 136.8, 138.2,139, 8, 141.1, 197.8; LC/MS (ESI): M⁺, found 389.18, C₂₈H₂₃NO requires389.18.

Example 13 Preparation of(R)-3-(1H-Indol-3-yl)-1-phenyl-3-(thiophen-2-yl)propan-1-one (3k)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2k(91 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP2.Purification by chromatography on silica (EtOAc/hexane 1:9) yieldedcompound 3k as a white solid (91 mg, 65%). Enantiomeric excess wasdetermined by chiral HPLC (Chiracel OD-H), hexane:i-PrOH 80:20, 0.4mL/min, λ=220 nm, t_(r)(minor)=3.1 min, t_(r)(major)=8.6 min, to be89.8%; m.p. 112-115° C., [α]²⁵ _(D)=+6.3 (c, 0.45, CHCl₃); [Anal. calcd.for C₂₁H₁₇NOS: C, 76.10; H, 5.17; N, 4.23. Found C, 75.89; H, 5.31; N,4.43]. IR (KBr): 3419, 1676, 1594, 1456, 741, 576 cm⁻¹; ¹H-NMR (CDCl₃,400 MHz) δ 3.84 (t, J=6.6 Hz, 2H, COCH ₂), 5.37 (t, 1H, J=6.6 Hz,ArCHCH₂), 6.85-6.98 (m, 2H, ArH), 7.02-8.65, (m, 9H, ArH), 7.92-7.94 (m,2H, ArH), 7.99 (s, NH of Indole); ¹³C-NMR (CDCl₃, 100 MHz): δ 33.6,46.2, 111.3, 116.1, 119.5, 119.6, 121.9, 122.3, 123.5, 124.3, 126.6,128.2, 128.7, 133.2, 136.0, 136.4, 143.9, 148.8, 198.1; LC/MS (ESI): M⁺,found 331.11, C₂₁H₁₇NOS requires 331.10.

Example 14 Preparation of3-(2,4-dichlorophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (3l)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2l(117 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP2.Purification by chromatography on silica gel column (EtOAc/hexanes 1:9)yielded compound 3l as an off-white solid (141 mg, 84%). Enantiomericexcess was determined by chiral HPLC (Chiracel OD-H), hexane:i-PrOH80:20, 0.4 mL/min, λ=220 nm, t_(r)(major)=8.3 min, t_(r)(major)=9.7 min,to be 97.5%; m.p. 110-112° C., [α]²⁵ _(D)=+8.7 (c, 0.45, CHCl₃); [Anal.calcd. for C₂₃H₁₇ClNO: C, 70.06; H, 4.35; N, 3.55. Found C, 69.91; H,4.29; N, 3.43]. IR (KBr): 3380, 2945, 1676, 1501, 1165, 1053, 745, 572cm⁻¹; ¹H-NMR (CDCl₃, 400 MHz) δ 3.71 & 3.74 (dd, 1H, J=14.0 Hz, 5.6 Hz,COCH _(2(a))), 3.97 & 4.01 (dd, 1H, J=14.0 Hz, 6.0 Hz, COCH _(2(b))),5.27 (t, 1H, J=5.6 Hz, ArCHCH₂), 6.90 (t, 1H, J=5.8 Hz, ArH), 7.02 (t,1H, J=6.0 Hz, ArH), 7.26-7.31 (m, 3H, ArH), 7.38 (d, 1H, J=6.4 Hz, ArH),7.44 (d, 1H, J=6.8 Hz, ArH), 7.50 (t, 2H, J=6.0 Hz, ArH), 7.54 (d, 1H,J=2.4 Hz, ArH), 7.62 (t, 1H, J=8.4 Hz, ArH), 7.99 (d, 2H, J=4.0 Hz, ArH_((orthoproton))), 10.91 (s, 1H, NH of Indole); ¹³C-NMR (CDCl₃, 100MHz): δ 33.27, 43.72, 111.34, 116.23, 117.93, 118.60, 121.24, 123.12,126.18, 127.38, 128.10, 128.22, 128.73, 128.91, 130.52, 131.15, 133.46,136.34, 136.58, 141.51, 197.90; LC/MS (ESI): M⁺, found m/z 393.10,C₂₃H₁₇ClNO requires 393.07.

Example 15 Preparation of3-(2,6-dichlorophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (3m)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2m(117 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica gel column (EtOAc/hexanes 1:9)yielded compound 3m as an off-white solid (133 mg, 78%). Enantiomericexcess was determined by chiral HPLC (Chiracel OD-H), hexane:i-PrOH80:20, 0.4 mL/min, λ=220 nm, t_(r)(minor)=8.3 min, t_(r)(major)=9.8 min,to be 81.7%; m.p. 119-121° C., [α]²⁵ _(D)=+1.7 (c, 0.45, CHCl₃); [Anal.calcd. for C₂₃H₁₇ClNO: C, 70.06; H, 4.35; N, 3.55. Found C, 70.13; H,4.46; N, 3.29]. IR (KBr): 3409, 2927, 1681, 1519, 1248, 1029, 741, 567cm⁻¹; ¹H-NMR (CDCl₃, 400 MHz) δ 4.03 & 4.06 (dd, 1H, J=13.6 Hz, 6.0 Hz,COCH _(2(a))), 4.24 & 4.28 (dd, 1H, J=14.0 Hz, 5.6 Hz, COCH _(2(b))),5.27 (t, 1H, J=6.0 Hz, ArCHCH₂), 6.81 (t, 1H, J=6.0 Hz, ArH), 6.98 (t,1H, J=5.6 Hz, ArH), 7.11 (d, 1H, J=6.4 Hz, ArH), 7.21 (t, 2H, J=6.4 Hz,ArH), 7.30 (d, 1H, J=6.8 Hz, ArH), 7.32 (d, 1H, J=0.8 Hz, ArH), 7.52 (t,3H, J=6.0 Hz, ArH), 7.63 (t, 1H, J=6.0 Hz, ArH), 7.99 (d, 2H, J=6.0 Hz,ArH _((orthoproton))), 10.92 (s, 1H, NH of Indole); ¹³C-NMR (CDCl₃, 100MHz): δ 34.12, 41.85, 111.91, 113.67, 115.92, 118.49, 120.88, 123.94,126.43, 128.04, 128.10, 128.85, 131.42, 131.95, 133.51, 136.24, 136.58,138.36, 198.18; LC/MS (ESI): M⁺, found m/z 393.10, C₂₃H₁₇ClNO requires393.07.

Example 16 Preparation of3-(1H-indol-3-yl)-1-phenyl-3-(m-tolyl)propan-1-one (3n)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2n(94.5 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica gel column (EtOAc/hexanes 1:9)yielded compound 3n as an off-white solid (114 mg, 79%). Enantiomericexcess was determined by chiral HPLC (Chiracel OD-H), hexane:i-PrOH80:20, 0.4 mL/min, λ=220 nm, t_(r)(minor)=9.1 min, t_(r)(major)=9.8 min,to be 72.4%; m.p. 130-132° C., [α]²⁵ _(D)=+3.3 (c, 0.45, CHCl₃); [Anal.calcd. for C₂₄H₂₁NO: C, 84.92; H, 6.24; N, 4.13. Found C, 85.03; H,6.11; N, 3.98]. IR (KBr): 3419, 1678, 1459, 1226, 1044, 741, 681 cm⁻¹;¹H-NMR (CDCl₃, 400 MHz) δ 2.20 (s, 3H, CH ₃), 4.74 & 3.77 (dd, 1H,J=13.6 Hz, 6.0 Hz, COCH _(2(a))), 3.88 & 3.92 (dd, 1H, J=14.0 Hz, 5.6Hz, COCH _(2(b))), 4.80 (t, 1H, J=6.0 Hz, ArCHCH₂), 6.88 (t, 2H, J=6.0Hz, ArH), 6.99 (t, 1H, J=6.0 Hz, ArH), 7.08 (t, 1H, J=5.6 Hz, ArH),7.17-7.19 (m, 2H, ArH), 7.27 (d, 1H, J=6.4 Hz, ArH), 7.30 (d, 1H, J=2.0Hz, ArH), 7.40 (d, 1H, J=6.4 Hz, ArH), 7.49 (t, 2H, J=6.0 Hz, ArH), 7.60(t, 1H, J=6.0 Hz, ArH), 7.99 (d, 2H, J=6.0 Hz, ArH _((orthoproton))),10.89 (s, 1H, NH of Indole); ¹³C-NMR (CDCl₃, 100 MHz): δ 20.60, 37.61,44.01, 11.31, 115.13, 118.21, 118.33, 119.95, 120.00, 126.39, 128.02,128.09, 128.70, 130.52, 133.65, 134.71, 136.38, 136.90, 139.83, 138.43,142.22, 198.49; LC/MS (ESI): M⁺, found m/z 339.10, C₂₄H₂₁NO requires339.16.

Example 17 Preparation of3-(1H-indol-3-yl)-1-(naphthalen-2-yl)-3-(thiophen-2-yl)propan-1-one (3o)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2o(112 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica gel column (EtOAc/hexanes 1:9)yielded compound 3o as an off-white solid (145 mg, 89%). Enantiomericexcess was determined by chiral HPLC (Chiracel OD-H), hexane:i-PrOH80:20, 0.4 mL/min, λ=220 nm, t_(r)(major)=10.217 min,t_(r)(minor)=14.345 min, to be 93.2%; m.p. 111-112° C., [α]²⁵ _(D)=+11.6(c, 0.45, CHCl₃); [Anal. calcd. for C₂₅H₁₉NOS: C, 78.71; H, 5.02; N,3.67. Found C, 79.01; H, 5.09; N, 3.51]. IR (KBr): 3410, 1675, 1585,1445, 1183, 739, 579, cm⁻¹; ¹H-NMR (CDCl₃, 400 MHz) δ 3.98-4.08 (m, 2H,COCH ₂), 5.22 (t, 1H, J=6.0 Hz, ArCHCH₂), 6.86 (t, 2H, J=4.0 Hz, ArH),6.93 (t, 1H, J=6.4 Hz, ArH), 6.99-7.05 (m, 2H, ArH), 7.21 & 7.22 (dd,1H, J=4.0 Hz, 1.2 Hz, ArH), 7.31 (d, 1H, J=6.8 Hz, ArH), 7.34 (d, 1H,J=1.6 Hz, ArH), 7.50 (d, 1H, J=6.4 Hz, ArH), 7.59-7.66 (m, 2H, ArH),7.94-7.99 (m, 2H, ArH), 8.11 (d, 1H, J=5.6 Hz, ArH), 8.77 (s, 1H, ArH),10.87 (s, 1H, NH of Indole); ¹³C-NMR (CDCl₃, 100 MHz): δ 32.49, 45.32,111.52, 114.43, 117.76, 118.49, 119.12, 121.08, 122.24, 123.63, 123.94,126.02, 126.55, 127.10, 127.68, 128.31, 128.75, 129.81, 130.20, 132.10,134.10, 135.55, 136.16, 149.77, 197.98; LC/MS (ESI): M⁺, found m/z381.2, C₂₅H₁₉NOS requires 381.12.

Example 18 Preparation of3-(1H-indol-3-yl)-3-(3-nitrophenyl)-1-phenylpropan-1-one (3p)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2p(129 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica gel column (EtOAc/hexanes 1:9)yielded compound 3p as an off-white solid (153 mg, 86%). Enantiomericexcess was determined by chiral HPLC (Chiracel OD-H), hexane:i-PrOH80:20, 0.4 mL/min, λ=220 nm, t_(r)(minor)=9.137 min, t_(r)(major)=10.186min to be 97.2%; m.p. 105-107° C., [α]²⁵ _(D)=+9.4 (c, 0.45, CHCl₃);[Anal. calcd. for C₂₃H₁₈N₂O₃: C, 74.58; H, 4.90; N, 7.56. Found C,74.63; H, 5.11; N, 7.47]. IR (KBr): 3414, 1677, 1536, 1357, 1276, 1133,724, 519 cm⁻¹; ¹H-NMR (CDCl₃, 400 MHz) δ 3.92-4.04 (m, 2H, COCH ₂), 5.02(t, 1H, J=6.0 Hz, ArCHCH₂), 6.89 (t, 1H, J=6.0 Hz, ArH), 7.02 (t, 1H,J=6.0 Hz, ArH), 7.30 (d, 1H, J=5.6 Hz, ArH), 7.44-7.54 (m, 5H, ArH),7.61 (t, 1H, J=6.0 Hz, ArH), 7.92-7.95 (m, 2H, ArH), 8.01 (d, 2H, J=5.6Hz, ArH), 8.22 (s, 1H, ArH), 10.91 (s, 1H, NH of Indole); ¹³C-NMR(CDCl₃, 100 MHz): δ 37.12, 44.00, 111.87, 117.18, 118.63, 121.08,121.56, 122.29, 126.16, 128.08, 128.22, 128.63, 128.83, 129.53, 133.71,134.92, 136.39, 136.70, 139.81, 142.22, 198.10; LC/MS (ESI): M⁺, foundm/z 370.2, C₂₃H₁₈N₂O₃ requires 370.13.

Example 19 Preparation of3-(4-bromophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (3q)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2q(143 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica gel column (EtOAc/hexanes 1:9)yielded compound 3q as an off-white solid (158 mg, 82%). Enantiomericexcess was determined by chiral HPLC (Chiracel OD-H), hexane:i-PrOH80:20, 0.4 mL/min, λ=220 nm, t_(r)(minor)=8.810 min, t_(r)(major)=9.712min, to be 87.2%; m.p. 95-97° C., [α]²⁵ _(D)=+2.8 (c, 0.45, CHCl₃);[Anal. calcd. for C₂₃H₁₈BrNO: C, 68.33; H, 4.49; N, 3.46. Found C,68.03; H, 4.69; N, 3.34]. IR (KBr): 3366, 1681, 755, 585, 503 cm⁻¹;¹H-NMR (CDCl₃, 400 MHz) δ 4.79 & 3.82 (dd, 1H, J=13.6 Hz, 6.0 Hz, COCH_(2(a))), 3.88 & 3.91 (dd, 1H, J=14.0 Hz, 5.6 Hz, COCH _(2(b))), 4.83(t, 1H, J=6.0 Hz, ArCHCH₂), 6.88 (t, 1H, J=6.4 Hz, ArH), 7.01 (t, 1H,J=6.0 Hz, ArH), 7.28 (d, 1H, J=6.4 Hz, ArH), 7.34-7.39 (m, 6H, ArH),7.50 (t, 2H, J=6.0 Hz, ArH), 7.61 (t, 1H, J=6.0 Hz, ArH), 7.99 (d, 2H,J=5.6 Hz, ArH), 10.86 (s, 1H, NH of Indole); ¹³C-NMR (CDCl₃, 100 MHz): δ36.34, 44.02, 111.91, 117.55, 118.43, 118.64, 119.10, 121.13, 122.15,126.10, 128.08, 128.73, 130.13, 130.94, 133.22, 136.41, 136.79, 144.78,198.24; LC/MS (ESI): M⁺, found m/z 403.1, C₂₃H₁₈BrNO requires 403.06.

Example 20 Preparation of3-(3-bromophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-one (3r)

Oxazoline-imidazoline ligand L (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)₂(15 mg, 0.042 mmol, 20 mol %), indole (50 mg, 0.425 mmol) and enone 2r(143 mg, 0.425 mmol) in CH₃CN (3 mL) were reacted according to GP1.Purification by chromatography on silica gel column (EtOAc/hexanes 1:9)yielded compound 3r as an off-white solid (162 mg, 84%). Enantiomericexcess was determined by chiral HPLC (Chiracel OD-H), hexane:i-PrOH80:20, 0.4 mL/min, λ=220 nm, t_(r)(minor)=9.211 min, t_(r)(major)=10.356min, to be 89.1%; m.p. 102-104° C., [α]²⁵ _(D)=+5.3 (c, 0.45, CHCl₃);[Anal. calcd. for C₂₃H_(1s)BrNO: C, 68.33; H, 4.49; N, 3.46. Found C,68.17; H, 4.53; N, 3.29]. IR (KBr): 3363, 1683, 744, 587, 501 cm⁻¹;¹H-NMR (CDCl₃, 400 MHz) δ 3.80 & 3.84 (dd, 1H, J=13.6 Hz, 6.4 Hz, COCH_(2(a))), 3.92 & 3.95 (dd, 1H, J=14.0 Hz, 5.6 Hz, COCH _(2(b))), 4.85(t, 1H, J=6.0 Hz, ArCHCH₂), 6.88 (t, 1H, J=6.0 Hz, ArH), 7.01 (t, 1H,J=6.0 Hz, ArH), 7.18 (t, 1H, J=6.4 Hz, ArH), 7.28 (t, 2H, J=5.6 Hz,ArH), 7.37 (d, 1H, J=2.0 Hz, ArH), 7.44 (d, 2H, J=6.4 Hz, ArH), 7.50 (t,2H, J=6.0 Hz, ArH), 7.57 (s, 1H, ArH), 7.67 (t, 1H, J=6.0 Hz, ArH), 8.00(d, 2H, J=5.6 Hz, ArH), 10.87 (s, 1H, NH of Indole); ¹³C-NMR (CDCl₃, 100MHz): δ 37.01, 44.04, 111.95, 117.48, 118.49, 121.01, 121.54, 122.10,124.10, 126.26, 127.03, 128.13, 128.75, 129.61, 130.32, 130.56, 133.64,136.32, 136.79, 148.33, 198.23; LC/MS (ESI): M⁺, found m/z 403.2,C₂₃H₁₈BrNO requires 403.06.

It is to be understood that the present invention is not limited to theembodiments described above, but encompasses any and all embodimentswithin the scope of the following claims.

1. A compound of Formula I:

wherein R₁ is 2,4-di chloro phenyl, 2,6-di chloro phenyl, bromo phenyl,methyl benzene, or nitrophenyl; and R₂ is an aryl group, orstereoisomers or pharmaceutically acceptable salts thereof.
 2. Thecompound according to claim 1, wherein the aryl group of R₂ is phenyl ora substituted or unsubstituted naphthyl group.
 3. The compound accordingto claim 1, wherein R₁ and R₂ are as provided in Table below. R₁ R₂—C₆H₃(2,4-di Cl) —C₆H₅ —C₆H₃(2,6-di Cl) —C₆H₅ —C₆H₄(4-Br) —C₆H₅—C₆H₄(3-Br) —C₆H₅ —C₆H₄(O₂N) —C₆H₅


4. A pharmaceutical composition, comprising the compound of claim 1 anda pharmaceutically acceptable carrier.
 5. A method for preparing thecompound of claim 1, the method comprising: (a) mixing a solution ofCu(OTf)2 and a ligand in dry acetonitrile under an inert atmosphere toform a first mixture; (b) adding to the first mixture a solution ofindole and a conjugated ketone in dry acetonitrile to form a reactionmixture; (c) stirring the reaction mixture at ambient temperature forabout 24 hours to about 48 hours; (d) removing a solvent from thereaction mixture in vacuo; (e) extracting the mixture using an organicsolvent.
 6. The method of claim 7 further comprising washing the mixturewith brine and drying over MgSO₄ after extracting the mixture using theorganic solvent to isolate the compound of Formula I.
 7. The method ofclaim 6, wherein the organic solvent is ethyl acetate.
 8. The method ofclaim 6, wherein the inert atmosphere is argon atmosphere.
 9. The methodof claim 6, wherein the ligand is oxazoline-imidazoline.